Macrophage-like vascular smooth muscle cells dominate early atherosclerosis and are inhibited by targeting iron regulation

Vascular smooth muscle cells (VSMCs) contribute dynamically to atherosclerosis at all stages but the molecular drivers of their phenotypic switching, especially during early plaque development, and how they contribute to plaque progression remain unclear. We performed spatial transcriptomics on 12 human aortic tissues with and without atherosclerotic plaque. Macrophage-like SMCs were the predominant cell-type in the atheroma, displaying high iron storage and dysregulation, confirmed by spatial elemental mapping with nuclear microscopy. The combination of soluble iron and oxidized LDL promoted foamy macrophage-like VSMC cell state transition, while chelation inhibited this switching. In vivo, iron dysregulation induced neointimal thickening and macrophage-like switching in wire-injured Ldlr-/- mice, which was significantly reversed by ferrostatin-1, a ferroptosis inhibitor. These data show how targeting iron regulation modifies the macrophage-like VSMC cell state, and inhibits disease progression in atherogenesis.